IT8048597A1 - PROCEDURE FOR PREPARING SI 3-SUBSTITUTED CEPHALOSPORIN AND PRODUCT OBTAINED. - Google Patents

Description

DESCRIPTION

accompanying a patent application for an invention entitled:

"Process for the preparation of 3-substituted cephalosporins and product obtained"

SUMMARY

In the present invention a process for the production of an enamine of the formula is described; IX:

where R2? a protecting group of carboxylic acid and? the residue of an acyl group derived from carboxylic acid where and are identical or different and are alkyl groups having from 1 to 4 carbon atoms or aralkyl groups of 7 to 10 carbon atoms; or taken together with the adjacent nitrogen atom they form a heterocyclic ring which contains from 4 to 8 carbon atoms and optionally a further heteroatom selected from oxygen and nitrogen; by reacting a compound of formula XII:

with an amine of the formula the reagent of the formula XII being prepared by means of the reaction of an appropriate? -olic derivative with a phosphorus reagent. The enamines of formula IX are useful in the preparation of 3-hydroxycephalosporins

DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for producing 3-substituted cephalosporin derivatives and includes within it original intermediates which are useful in said process.

Lately ? It has been found that 3-hydroxycephalosporins can be converted into their corresponding 3-alkoxy- and 3-chloro-derivatives and that said chloro- and alkoxy-derivatives are extremely efficient as antibacterial agents (see British Patent Descriptions No. 1,454,399 and No.

1,546,221, and U.S. Patent No. 4.O64. 343). Therefore, much research effort has been devoted to the development of economically viable production processes for 3-hydroxycephalosporins. Perhaps the best procedure so far described in lecture? what appears in Example 17-3 of U.S. Pat. No. 4,079. 181 which procedure can? be schematically illustrated by the following reaction program:

(formulas follow)

wherein R represents an ester protecting group. para-nitrobenzyl

Can't you? deny that this technique constitutes an extremely valid way to obtain the derivative of formula V of 3-hydroxycephalosporin. However in the present invention? It has been found that the yield of the product (II) obtained in the functionalization of the enol (formula I) is considerably reduced (of the order of 10%) by the formation of the C-mesylate product of the formula VI:

So ; the maximum achievable yield of the compound of formula V is reduced by 10% and, of course, the production of the undesired C-mesylate product dar? as a result purification problems during the consecutive treatment of the intermediate mixture (II) and (Vl) as well as may? to influence in a contrary way the stoichiometry of the further stages of the reaction in the synthesis of the molecule of the formula V of 3-hydroxy-cefem.

In the present invention? It has been found that surprisingly, the functionalization of enol (formula I) occurs exclusively on the oxygen atom if the methanesulfonyl chloride is replaced by a phosphorus reactive of the form

mule VII:

where they are identical or different and can each represent a phenyl group or a phenoxy group optionally substituted with a number of groups ranging from 1 to 3 selected from an alkyl radical of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms , halogen and nitro group; or they are alkyl groups having from 1 to 4 carbon atoms, alkoxy groups of 1 to 4 carbon atoms, cycloalkyl groups of 3 to 8 carbon atoms, cycloalkoxy groups of 3 to 8 carbon atoms, chlorine or bromine;

X? chlorine, bromine, nitrile or azide; provided that:

i) can't both be alo?

geno; And

ii) when X? a nitrile radical or? an azide, they are identical or different and are phenoxy radicals; cycloalkoxy groups of 3 to 8 carbon atoms or alkoxy groups of 1 to 4 carbon atoms.

Preferably, the reagent of formula VII? that in which R and R are phenoxy radicals optionally substituted with a number of groups ranging from 1 to 3 selected from the alkyl radicals having from 1 to 4 carbon atoms, alkoxy radicals of 1 to 4 carbon atoms, halogen and nitro groups; alkoxy radicals of 1 to 4 carbon atoms or cycloalkoxyl radicals of 3 to 8 carbon atoms and X? a bromine atom or a chlorine atom.

In the present invention? it was now discovered that the product cos? format pu? be converted to the corresponding enamine derivative with high yield under mild conditions. The enamine derivative pu? be converted to the corresponding 3-hydroxyfem of formula V using the reaction conditions described in U.S. Patent No. 4-079.181.

Those skilled in the art will appreciate that in view of the extremely high cost involved in preparing cephalosporins, yield increases of even a few percent can have a major influence on the factors of the economy of production, and therefore? the validity? commercialization of this type of antibiotic.

The present invention provides a process for the production of a 3-hydroxy-cephalosporin of formula VIII:

where is it ? a protecting group of a carboxylic acid and together with the associated carbonyl group,? an acyl group derived from carboxylic acid which process comprises:

a) the halogenation of a compound of formula IX

where they are identical or different and are alkyl groups of up to 4 carbon atoms or aralkyl groups of 7 to 10 carbon atoms; or together with the adjacent nitrogen atom and form a heterocyclic ring which contains from 4: to 8 carbon atoms and optionally a further hetero atom which is selected from oxygen and nitrogen;

b) cyclization of the halogenated product of formula X:

where X? an atom of chlorine, bromine or iodine, of (a) in 3-hydroxy-cephalosporin corresponding to formula XIII in which the compound of formula IX is prepared by

c) reaction of an enol corresponding to formula XI

with a phosphorus reagent corresponding to the formula VII:

where and X are as gi? in precedence? been defined, so as to form a product of the formula XII:

operation followed by the reaction of this product with an amine of the formula to form the amine starting material of the formula IX used in step (a).

The reaction of the enol of formula XI with the phosphorated reagent of formula VII and the reaction of the product of formula XII with the amane of formula are both original and inventive and are therefore? provided individually and in combination as further aspects of the present invention.

For the ease? structures, and to facilitate understanding of the present invention, structures possessing a double bond in the lateral catheha have been shown in only one of their stereoisomeric forms. However, those skilled in the art will readily appreciate that these structures may exist in the alternative form and where this possibility exists, it should be clearly understood that such alternative forms are all concerned within the scope of the present invention.

The acyl group derived from carboxylic acid can? be any of those groups that are conventionally used in the beta-lactam branch, the nature of which groups will be? readily apparent to those skilled in the art. So, for example the residue

can ffisere:

a) hydrogen, an alkyl group having from 1 to 3 carbon atoms, a methyl halogen group, cyano methyl or 3- (2-chlorophenyl) -5-methylisoxazol-4-yl.

b) benzyloxy, 4-nitrobenzyloxy, 2,2,2-trichloro and toxyl, tert-butoxy or 4-methoxybenzyloxy.

c) The group in which? a phenyl group or a phenyl group substituted with a number of substituents equal to 1 or 2, independently chosen from the group formed by the halogen, protected hydroxyl radical, nitro group, cyano group, trifluoromethyl group, alkyl group having from 1 to 3 atoms of carbon and alkoxy group having from 1 to 4 carbon atoms;

d) an arylalkyl group of the formula:

where R? ? R "as above has already been defined, 2-thienyl, 3-thienyl or 1, 4-cyclohexyldienyl, m? 0 or 1 and Q? 0 or S, but always with the limitation according to which when m? 1, then R? R ";

e) a substituted arylalkyl group of the formula:

where R? like above ? been defined and W? a hydroxyl group, protected hydroxyl, amino group, protected amino group, or protected carboxylic group; that is to say

f) a heteroaryl alkyl group of the formula e 2-furyl, 3-furyl, 2-thiazolyl, 5-isoxazolyl or 5-tetrazolyl

In the foregoing description, the term alkyl radical having from 1 to 3 carbon atoms "refers to methyl, ethyl, n-propyl or isopropyl groups Representative" alkyl alkyl groups of 1 to 4 carbon atoms "are the methoxy, ethoxyl group , n-propoxyl and tert-butoxy.

Halogen methyl "represents chlorine methyl, bromo methyl, fluoro methyl and iodo methyl.

When in the above definition R "represents a substituted phenyl group, R" pu? being a mono- or di-substituted phenyl halogen group such as 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3, 4-dibromophenyl, 3-chloro-4-fluorophenyl, 2-fluorophenyl and the like; a protected hydroxyphenyl group such as for example 4-benzyloxyphenyl, 3-benzyloxyphenyl, 4-tert-butoxyphenyl, 4-tetrahydropyranyloxyphenyl, 4- (4-nitrobenzyloxy) -phenyl, 2-phenacyloxyphenyl, 4-benzyloxyphenyl, 4-trityloxyphenoxy , and similar other groups; a nitrophenyl group such as 3-nitrophenyl or 4-nitrophenyl; a cyanophenyl group such as the 4-cyanophenyl group; a mono- or di-alkyl substituted phenyl group such as 4-methylphenyl, 2,4-dimethylphenyl, 2-ethylphenyl, 4-isopropylphenyl, 4-ethylphenyl, 3-n-propylphenyl similar; a mono- or di-alkoxyphenyl group, such as 2,6-dimethoxyphenyl, 4-methoxyphenyl, 3-ethoxyphenyl, 4-isopropoxyphenyl, 4-tert-butoxyphenyl, 3-ethoxy-4-methoxyphenyl and the like. Furthermore, R "represents disubstituted phenyl groups in which the substituents are different such as 3-methyl-4-ethoxyphenyl, 3-chloro-4-benzyloxyfertile, 2-methoxy-4-bromophenyl, 4-ethyl-2-methoxyphertile, 3- chloro-4-nitrophenyl, 2-methyl-4-chlorophenyl and the like and other disostite phenyl groups bearing different substituents.

The term "protected amino group '' as used in the previous description refers to an amino group substituted with one of the groups commonly used to block amino groups such as for example the tertzbutoxycarbonyl group; the benzyloxycarbonyl group, the methoxybenzyloxycarbonyl, the 4-nitrobenz group : oxycarbonyl, the 2,2,2-trichloroethoxycarbonyl group or the 1-carbomethoxy-2-propenyl group formed with methyl acetoacetate. Analogous protective groups of the amino groups with respect to those described above, are those described by J.W. Barton in Protective Groups in Organic Chemistry J.F. W. McOmie, Ed. Plenum Press, Few York, F.Y. 1973, chapter 2. which will also be recognized as suitable.

The term "protected hydroxyl group" refers to easily detachable groups formed with a hydroxyl group such as a formyloxy group, the chloroacetoxyl group, the benzyloxy group, the benzhydryloxy group, the trityloxy group, the 4-nitrobenzyloxy group, the trimethylsilyloxy group , the phenoxy group, the tertiary butoxy group, the methoxymethoxy group, the tetra-dropyranyloxy group and the like. Other protective groups of the hydroxyl groups with the inclusion of those described by C.B. Reese in "Protective Groups in Organic Chemistry", supra, chapter 3, can be considered as being within the term "protected hydroxyl group" as used herein.

R3? preferably a benzyl radical or a phenoxymethyl radical

The R group? a proective group of carboxylic acid. This term refers to the protective groups of carboxylic acids, which are commonly used, to block or protect the functionality? carboxylic acid while reactions are conducted which include other functional active centers d ?. compound itself. Such protective groups of the carboxylic radical are noted for their easiness. of cleavage by means of hydrolysis or hydrogenolysis processes, cos? to obtain the corresponding carboxylic acid. Examples of protective groups of carboxylic acid esters include methyl, tert-butyl, benzyl 4-methoxybenzyl, alkanoyloxymethyl _2-iodoethyl, para-nitrobenzyl, diphenylmethyl (benzhydryl), phenacyl, 4-halophenacyl, dimethylallyl, 2,2,2-trichlorethyl , tri (alkyl

xylyl, methyl succinimido and similar other esters forming parts. Other protective groups already? known carboxyl radicals such as those described by E, Haslam in? Protective Groups in Organio Chemistry ", supra, chapter 5, will also be recognized as suitable. The nature of such ester-forming groups is not critical although it has been found herein. invention that the impact of the para-nitrobenzyl protecting group is particularly desirable.

In the definitions that proceed, the protective groups of hydroxyl, amino and carboxylic radicals are not exhaustively defined, the function of these groups? that of protecting the reactive functional groups, for example during the preparation of the starting materials, and to be removed at a later time without destroying the remaining part of the molecule. Many of these protective groups are already? well known in the related branch and the use of other groups? equally applicable to the process and compounds of the present invention will be recognized as suitable. So, isn't there? any news? or inventiveness? in the statement regarding the so-called protective groups referred to in the present description.

Representative examples of the acylamine group in the compound of formula VIII are the formamide, acetamido, propionamido, butyramido, 2-pentenoylamino, cyanacetamido, chloracetamido, bromoacetamido, 5-tert-butoxycarbonylamino groups, and 5-tert-butoxycarbonyl valeramido.

Illustrative examples of the particular acylammic group

are the group benzamido, 2,6-dimethoxybenzamido, 4-chlorobenzamido, 4-methylbenzamido, 3,4-dichlorobenzamido, 4-cyanobenzamido, 3-bromobenzamido and 3-nitrobenzamido.

Examples of the acylamine group

when R3? a group of the formula

and m? 0, are cilohexa-1,4-dienylacetamido, phenylacetamido, 4-chlorophenylacetamido, 3-methoxyphenylacetamido, 3-cyanophenylacetamido, 3-methylphenylacetamido, 4-bromophenylacetamido, 4-ethoxyphenylacetamido-nitamido, 4-ethoxyphenylacetamido-dimido-thienifamido 3-thienylacetamido and the like; when ra? 1 and Q? 0, representative acylamine groups are phenoxyacetamido, 4-cyanophenoxyacetamido, 4-chlorophenoxyacetamido, 3, 4-dichlorophenoxyacetamido, 2-chlorophenoxyacetamido, 4-methoxyphenoxyacetamido, 2-ethoxyphenoxyacetamido, 3-methoxyphenoxyacetamido, 3-dimethyl methoxyacetylacetamido, 3-phenoxyphenoxyacetamido nitrophenoxyacetamido and similar other substituted phenoxyacetamide groups; and when m? 1 and Q? S, representative groups are phenylthioacetamido, 2,5-dichlorophenylthioacetamido, 4-bromophenylthioacetamido, 4-methoxyphenylthioacetamido, 4-tolylthioacetamide and similar other substituted phenylthioacetamide groups.

Illustrative examples of acylamine groups when R3? a substituted arylalkyl group of the formula:

and when W? protected hydroxyl groups are 2-formyloxy-2-phenylacetamido, 2-benzyloxy-2- (4-methoxyphenyl) acetamido, 2- (4-nitrobenzyloxy) -2- {3-chlorophenyl) acetamido, 2-chloroacetoxy-2- ( 4-methoxy

phenyl) acetamido, 2-benzyloxy-2-phenylacetamido, 2-trimethylsilyloxy-2- (4-chlorophenyl) acetamido, and 2-benzhydryloxy-2-phenylacetamido. Representative examples of such groups when W? a protected amino group are 2- (4-nitrobenzyloxycarbonylamino) -2-phenylacetamido, 2- (2, 2-trichloroethoxycarbonylamino) -2-phenylacetamido, 2-chloroacetamido-2- (1, 4-cyclohexadien-1-yl) acetamido, 2 - (4-methoxybenzyloxycarbonylamino) -2- (4-methoxyphenyl) acetamido, 2-benzhydryloxycarbonylamino-2-phenylacetamido, 2- (1-carbomethoxy-2-propenyl) amino-2-phenylacetamido and 2- (4-nitrobenzyloxycarbon ) -2- (2-thienyl) acetamido.

Examples of the acylamine group of the formula

when ? a heteroarylmethyl group of the formula are 2-furylacetamido, 3furylacetamido- a group -thiazolylacetamido of the formula

or a 5-isoxazolylacetamido group of the forula.

(follows fomula)

The compound corresponding to the formula IX pu? be halogenated using the reagents and conditions which have been specified in U.S. Pat. No. 4,079,181. Suitable halogenating reactants include those which halogen via the halogen cation or a halogen radical or its equivalent. Representative halogenating reagents belong to the pi? cited below:

alpha-halogenketone, alpha-halogenosulfones or similar other reactants, where the alkyl group and the acyl group contain up to 4 carbon atoms and? chlorine, bromine or iodine. ? preferably bromine.

When these halogenating reactants act through a halogen radical, the reaction can? be triggered by thermal action, light, peroxides (peracid, peroxide, hydroperoxide, etc ..), azo compounds (azobisisobutyronitrile, etc ..) or other radical initiator.

When these halogenating reagents act via a halogen cation, the reaction is preferably conducted in the presence of an acid trapping reagent (organic or inorganic base, e.g. sodium carbonate, pyridine, quinoline, lutidine, morpholine, diethylamine, triethylamine, etc..).

The reaction of the starting materials with the halogenating reagent? preferably carried out in an inert solvent. Suitable solvents include hydrocarbons (pentane, hexane, benzene, toluene, etc.), halogenated hydrocarbons (meiene chloride, chloroform, carbon tetrachloride, dichlorobenzene, etc.) esters (ethyl acetate, methyl butylene benzoate acetate, etc. ), ketones (acetone, cyclohexanone, benzophenone, etc.), ethers (diethyl ether, ethylene glycol heterimethyl ether, tetraedrofuran, tetrahydropyran, dioxane, anisole, etc.), alcohols (methanol, ethanol, ethylene glycol, benzyl alcohol, etc.) ), carboxylic acids (acetic acid, proionic acid, etc.), organic thases (butylamine, triethylamine, pyridine, picoline, etc.), organic amrnides (dimethylformamide, d? methylacetamide, hexamethylphosphorotriamide, etc.,) organic nitriles (acetonitrile, benzonitrile etc.), nitro-hydrocarbons and alkylsulfoxides (dimethylsulfoxide etc.)

Representative examples of suitable groups

are the group dimethylamino, diethylamino, methylethylamino, dipropylamino, dibutylamino, dibenzylamino, a, when the morpholino, piperidino and piperazino groups represent a cyclic part. The preferred group for use in the context of the present invention? the morpholino group.

The cyclization reaction (b) can? be carried out by acid catalyzed hydrolysis. Suitable solvents for the cyclization reaction are ether-type solvents such as tetrahydrofuran, tetr? Hydropyran and dioxane, amide solvents such as dimethylformamide, dimethylacetamide and hexamethylphosphorotriamide, halogenated hydrocarbon solvents such as chloroform and dichloroethane, aliphatic and aromatic esters, such as ethyl acetate, aliphatic ketones such as acetone, aliphatic and aromatic nitriles such as, for example, acetones

rile and alkyl sulfoxides such as dimethyl sulfoxide.

Suitable acids used for the acidification of the reaction medium include aqueous inorganic acids (e.g., hydrochloric acid, bromyric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, sulphurous acid), aqueous arylsulfonic acids such as para-toluenesulfonic acid and aqueous alkysulfonic acids such as methanesulfonic acid,

The reaction between the enob of formula XI and the phosphorus reagent of formula VII is preferably carried out at a temperature in the range from -30 ° C to 50 ° C and more. preferably from 0? C to 25? C. At these temperatures, the reaction? substantially complete in half an hour to six hours. Any suitable inert organic solvent can? be used. However, good results have been obtained using ethereal solvents such as diethyl ether, dimethyl ether and ethylene glycol, etheridrofuran, tetrahydropyran, dioxane and anisole. The use of tetrahydrofuran as an ethereal solvent? favorite. Furthermore, excellent results have been obtained using as solvent halogen alkanes such as methylene chloride, alkyl nitriles such as acetonitrile and alitatic esters such as ethyl acetate.

The condensation reaction between the enol and the osphorus compound proceeds through the elimination of X. The reaction? preferably carried out by operating in the presence of a base strong enough to generate the enolate anion such as for example a tertiary organic amine for example pyridine, triethylamine, N-methylmorpholine or quinoline.

n some circumstances can? it may be desirable to carry out the condensation reaction in the presence of an acylation catalyst and in such circumstances the catalyst employed may be being a 4-dialkylamino pyridine of the type described in the journal Angew. Chem. Int. Ed. Engl. 17 569-583 (1978)

The use of an inert gaseous atmosphere such as nitrogen? preferred.

Examples of suitable phosphorus compounds for use in the process to which the present invention relates are:

diphenylphosphoryl chloride

diphenylphosphoryl bromide

diethylphosphoryl chloride

diethylphosphoryl bromide

dibutylphosphoryl chloride

dibutylphosphoryl bromide

bis- (2-chlorophenyl) phosphoryl bromide bis- (3-chlorophenyl) phosphoryl chloride bis- (3-fluorophenyl) phosphoryl bromide bis- (4-iodophenyl) phosphoryl chloride bis- {2,3-dichlorophenyl ) bis- (3,4-dilorophenyl) phosphoryl chloride bis- (4-methylphenyl) phosphoryl bromide bis- (4-butylphenyl) phosphoryl chloride bis- (3,4-dimethylphenyl) bis- (3,4-dimethylphenyl) phosphoryl chloride (3-chloro-4-methylphenyl) phosphoryl chloride of bis- (3-methoxyphenyl) phosphoryl chloride of bis- (4-methoxyphenyl) phosphoryl chloride of bis- (3-bufoxyphenyl) phosphoryl chloride of bis- (4-nitrophenyl) phosphoryl bis- (3,4,5-trimethoxyphenyl) phosphoryl chloride

bis- (3,4,5-trimethoxyphenyl) phosoryl bromide

bis- (2-methoxy-3-methyl-4-fluorophenyl) -phosphoryl chloride

dicyclopropylphosphoryl chloride

dicyclopropylphosphoryl bromide

dicyclohexylphosphoryl chloride

bromuro di dicicloesilfosforile cloruro di dicicloottilfosforile bromuro di dicicloottilfosforile dimetilfosforilazide dimet?lfosforilcianuro dietilfosforilazide dietilfosforilcianuro difenilfosforilazide difenilfosforilcianuro dicicloesilfosforilazide dicicloesilfosforilcianuro bicloruro di metilfosforile dibromuro di metilfosforile bicloruro di etilfosforile dibromuro di etilfosforile bicloruro di propilfosforile bicloruro di isopropilfosforile bicloruro di butilfosforile bicloruro di fenifosforile dibromuro di fenilfosforile bicloruro di 2- chlorophenylphosphoryl dibromide of 2-chlorophenylphosphoryl dibromide of 3-chlorophenylphosphoryl dichloride of 3-fluoro phenylphosphoryl dibromide of 2,4-diclaophenylphosphoryl dibromide of 2, 4-dichlorophenyl dibromide of 3-chlorophylophoryl-dichlorophylo-di-3-chlorophoryl-dichlorophylo-dichlorophylo-di-3-di-chlorophylophoryl-dichlorophylo-diphoride 4-methylphenylphosphoryl dichloride of 3-methoxyphenylphosphoryl dichloride of 4-methoxyphenylphosphoryl dichloride of 3-butoxyphenylphosphoryl dichloride of 4-n 3, 4, 5 -trimethoxyphenylphosphoryl dichloride of cyclopropylphosphoryl dichloride of cyclopentyl

cyclohexylphosphoryl dichloride

dibromide of skyhexylphosphoryl

cyclooctylphosphoryl dichloride

methylmethylphosphonyl chloride

methylmethylphosphonyl bromide

methylphenylphosphonyl chloride

ethylmethylphosphonyl chloride

ethyl ethyl phosphonyl chloride

ethyl ethyl phosphonyl bromide

ethifenylphonyl chloride

ethyl 3-chlorophenylphosphonyl chloride ethyl 2, 4-dichlorophenylphosphonyl chloride ethyl 4-methylphenylphosphonyl chloride ethyl 4-methoxyphenylphosphonyl chloride

phenylmethylphosphonyl chloride

phenylenylphosphonyl chloride

fnylphenylphosphonyl bromide

phenyl 4-methylphenylphosphonyl chloride phenyl cyclohexylphosphonyl chloride

2,4-dichlorophenylethylphosphonyl chloride 2,4-dichlorophenylphenylphosphonyl chloride 2,4-dichlorophenylcyclohexylphosphonyl chloride 4-nitrophenylethylphosphonyl chloride

4-nitrophenylphenylphosphonyl chloride 4-nitrophenylcyclohexylphosphonyl chloride 3,4,5-trime toxiphenylethylphosphonyl chloride 3,4,5-trimethoxyphenylphenylphosphonyl cyclopentylethylphosphonyl chloride

cyclopentylphenylphonyl chloride

cyclohexylphenylphosphonyl chloride

dimethylphosfinyl chloride

dimethylphosfinyl bromide

diethylphosfinyl chloride

diethylphosfinyl bromide

dipropylphosfinyl chloride

diisopropylphosfinyl chloride

dibutylphosfinyl chloride

diphenylphosphinyl chloride diphenylphosphinyl bromide bis- (2-chlorophenyl) phosphinyl bromide bis- (2-chlorophenyl) phosphinyl chloride bis- (3-chlorophenyl) phosphinyl chloride bis- (3-fluorophenyl) phosphinyl chloride bis- (2,4-dichlorophenyl) phosphinyl bis- (3,4-dichlorophenyl) phosphinyl chloride bis- (4-methylphenyl) phosphinyl bis- (3-chloro-4-methylphenyl) phosphinyl clony

bis- (3-methoxyphenyl) phosphinyl chloride bis- (4-methoxyphenyl) phosphinyl chloride bis- (3-butoxyphenyl) phosphinyl chloride bis- (4-nitrophenyl) phosphinyl chloride bis- (3,4,5 -trimethoxyphenyl) phosphinyl dicyclopropylphosphinyl chloride dicyclopentylphoxynyl chloride dicyclohexylphosphinyl chloride dicyclohexylphosphinyl bromide, and dicyclooctylphosphinyl chloride.

The use of diphenylphosphoryl chloride as a phosphorus reagent? favorite,

The product of the condensation reaction? a compound corresponding to formula XII. Such compounds are original and are provided in a further aspect of the present invention. Representative examples of these original intermediates are cited below:

-

or

_ __ p The conversion of the intermediate of the formula XII to the amino starting material of the formula IX? preferably carried out at a temperature varying in the range from -10? C to 50? C and even more? preferably from 0? C to 5? C. Any suitable organic solvent can? be used for the conversion, in particular those mentioned above in connection with the reaction of the enol in formula XI and the phosphorus reactive of formula VII. The amine of the formula where e

are like gi? previously ? state defined should be used in the form of the free base.

A very great advantage of the process to which the present invention refers? consisting of the fact that since? the reaction conditions, the temperature, the solvent, etc., are very similar for each of the stages of the reaction, the whole technique can? be conducted "in a vessel".

In order to further illustrate the present invention and to show how it can be realized, it will come to pass. I have now referred to the following examples thereof which are of a non-limiting nature.

Example 1

para-nitrobenzi 7-phenylacetamido-3-hydroxy-3-cefem-4-carboxylate

To a stirred suspension of para-nitreben zil alpha- [3-benzyl-7-oxo-4-thia- -diazabicyclo [3,2,0] -ept- -en-6-yl] -alpha- (1-hydroheethylidene ) acetate (9.06 grams) in 120 ml of tetrahydrofuran under nitrogen atmosphere at a temperature of 20 ° C, 3.21 ml of triethylamine and 4.77 ml of diphenylphosphoryl chloride were added. The reaction mixture was stirred for 2 hours and then cooled to 0 ° C / Then 4.01 ml of morpholine were added and then the reaction mixture was stirred for 2 hours at 0 to 5 ° C. The reaction mixture was then cooled to a temperature of -30 to -35? and then 1.62 ml of pyridine was added, followed by 1.00 ml of bromine dropwise over a period of 10 minutes.

the reaction mixture was at 20 g at a temperature of -30 l -35 ° C and then 144 ml of 5% hydrochloric acid, 120 ml of ethanol and 20 ml of tetrahydrofuran were added. The reaction mix was still stirred at room temperature for 3 hours and then left at 0 ° C overnight. The product was then isolated by filtration and washed with 30 ml of methanol, 30 ml of water and 30 ml of methanol, and then dried under vacuum at a temperature of 40 ° C for 5 hours. The total yield of the corrosive field was 8.05 grams (86%).

Example 2

p ara-nit robenzil 7-phenos si ace tamide o -3- i d ro s si- 3-cefem-4-carbo s sil ato

To an agitated solution d? paranitrobenzyl alpha- [3-phenoxymethyl-7-oxo-4-thia-2, 6-diazabicyclo [3, 2, 0] hept-2-en-6 yl] -alpha- (1-hydroxyethylidene) acetate (9, 38 g) 3.21 ml triethylamine were added to 120 ml of tetrahydrofuran under nitrogen atmosphere at 20 ° C, followed by 4.77 ml of diphenylphosphoryl chloride. The reaction mixture was then stirred for 2 hours and then cooled to 0 ° C. Then 4.01 ml of morpholine were added and the reaction mixture was stirred for 2 hours at 0 to 5 ° C. The reaction mixture was subsequently cooled to -30 to -35 ° C and 1.62 ml of pyrin was then added followed by the dropwise addition of 1.00 ml of bromine over a period of 10 minutes. The reaction mixture was stirred at -30 to -35 ° C for 20 minutes and then 144 ml of 5% hydrochloric acid were added, followed by further stirring at room temperature at three hours. The reaction mixture was then allowed to stand overnight at 0 ° C. The reaction mixture was extracted with dichloromethane and the organic extracts were then washed with water and then with saturated sodium chloride solution, dried with magnesium sulfate and then evaporated to dryness. The product thus obtained dissolved in dichloromethane and then acetic acid was added, the dichloromethane removed under reduced pressure and then the ether was added with stirring so as to complete the crystallization. The product was then isolated by filtration, washed with ether, then dried under vacuum at 40 ° C for 5 hours. The yield of acetic acid solvate with para-nitrobenzyl-7-phenoxyacetamido -3-hydroxy-3-cephem-4-carboxylate was 9.16 grams (84%).

Example 1

2-en-6-yl) -alpha- (1-hydroxyethylidene) acetate (4.53 g) containing 4-dimethylamino pyridine (0.1 g) in 50 ml of ethyl acetate under nitrogen atmosphere at a temperature of 20? C 1.53 ml of triethylamine were added followed by the dropwise addition of 1.53 ml of ethylphosphoryl chloride. The reaction mixture was stirred at 20 ° C for 3 hours. Then 40 ml of water were added and the organic layer was separated washed with 20 ml of water and 20 ml of saturated sodium chloride solution, then dried with magnesium sulfate and then treated with charcoal, filtered and evaporated to give the compound corresponding to the title in the form of a viscous yellow oil in essentially quantitative yield. Thin layer chromatography (silica) gave Rf = 0.17 (dichloromethane / ethyl acetate = 15/2). The product consisted of a mixture of the geometric isomers (ratio of about 2/1) around the double bond of the enol phosphate. Nuclear magnetic resonance _

_

Example 4

nyl) -prop-1-en-2-phosphate

To a suspension of para-nitrobenzyl alpha- (3-benzyl-7-oxo-4-thia-2, 6-di azabicyclo [3, 2, 0] hept-2-en-6-yl) -alpha- (1 -hydroxyethylidene) acetate (4.5 3 g) in 60 ml of tetrahydrofuran under nitrogen atmosphere at 20 ° C, 1.53 µl of triethylamine were added followed by the addition carried out dropwise of 2.28 ml of diphenylphosphoryl chloride. The reaction mixture was stirred at 20 ° C for 2 hours. 50 ml of water were then added and the mixture was extracted with 60 ml of dichloromethane. The organic layer was separated, washed with water (30 ml) and saturated sodium chloride solution (30 ml), dried with magnesium sulfate, filtered and then evaporated to give the title compound in the form of a viscous yellow oil. with essentially quantitative yield. Thin layer chromatography (silica) Rf = 0.68 (dichloromethane / ethyl acetate = 15/2). The product consisted of a mixture of the geometric isomars (about 4/1) around the double bond of the enol phosphate. Nuclear magnetic resonance

wicked 5

Diphenyl 1- (3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3,2,0] hept-2-en-6-yl) -1- (para-nitrobenzyloxycarbonyl) -prop-1 -en-2-phosphate To a solution of para-nitrdbenzyl alpha- (3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicicl [3,2,0] -ept-2-en-6- the) -alpha- (1-hydroxyethylidene) acetate (9.38 g) in a volume of 100 ml of dichloromethane under nitrogen atmosphere at 20 ° C triethylamine was added, followed by the addition of diphenylphosphoryl chloride (4.35 ml) The reaction mixture was stirred at 20 ° C for 2 hours. Then 50 ml of water were added and the organic layer was separated, washed with 40 ml of water and saturated sodium chloride solution (40 ml), then dried with magnesium sulfate, filtered and then evaporated to give the compound corresponding to the title in the form of a viscous yellow oil with essentially quantitative yield. Thin layer chromatography of silica gave Rf = 0.60 (ethyl acetate). The product consisted of a mixture of the geometric isomers (about 3/1) around the double bond of the enol phosphate. separation by thin layer chromatography of these isomers could be obtained; Rf = 0.52 and 0.45 (toluene / ethyl acetate, 1/1). Nuclear magnetic resonance

Example 6

1- (para-nitrobenzyloxycarbonyl) -prop-1-en-2-i phosphate (5.90 g) in 70 ml of diloromethane at a temperature from 0 to 5 ° C, 1.83 ml of morpholine were added drop by drop and then the reaction mixture was stirred at this temperature for 2 hours. 40 ml of water were then added and the organic layer was separated, washed with 30 ml of water and a salty solution of sodium chloride (30 ml), dried with magnesium sulfate, filtered and then evaporated to give the compound corresponding to the title in the form of a yellow foam with almost quantitative yield. Thin layer chromatography of silica gave Rf = 9.60 (ethyl acetate). The product was a mixture of the geometric isomers (in the ratio of about 1/4) around the double bond of the enammia. Nuclear agnetic resonance

7.77 and 8.10-8.40 (m, 9H).

Example 7

Para-nitrobenzyl alpha- (3-benzyl-7-oxo-4-thia-2,6-diazaticyclo [3, 2,0] hept-2-en-6-i) -alpha- (1-morpholinoethylidene) acetate

To a solution of diphenyl - (3-benzyl-7-oxo-4-thia-2,6-diazabicyclo [3,2,0] hept-2-en-6-yl) -1- (para-nitrobenzoxycarbonyl) prop -1-en 2-ylphosphate (6.86 g) in 50 ml of acetonitrile at a temperature from 0 to 5 ° C 1.83 ml of morpholine were added dropwise and then the reaction mixture was stirred at this temperature for 2 hours. 50 ml of water were then added and the mixture was extracted with 40 ml of ethyl acetate. The organic layer was separated, washed with 30 ml of water and saturated sodium chloride solution (30 ml), dried with magnesium sulfate, filtered and then evaporated thus. to give the compound corresponding to the title in the form of a yellow foam with an almost quantitative yield. The product obtained was formed by a mixture of the geometric isomers (in the ratio of about 1 / 1.4) around the double bond of the enamine and was identical to that produced in example 6.

Example 8

Para-nitrobenzyl alpha- (3-phenoxymethyl-7-oxo-4-thia

2,6-diazabicic [lo 3, 2, 0 / hept-2-en-6-yl) -alpha- (1-morpholinoethylene) acetate

To a solution of diphenyl 1- (3-phenoxymethyl-7-oxo-4-thia-2, 6-diazabicyclo [3, 2, 0] hept-2-en-6? Yl) - 1 - (para-nitrobenzyloxycartonyl) -prop-1-en-2-yl phosphate (7.02 g) in ethyl acetate (70 ml) at a temperature from 0 to 5 ° C 1.83 ml of morpholin? were added dropwise. and then the reaction mixture was stirred at this temperature for 2 hours.

Then 30 ml of water were added and the organic layer was separated, washed with 30 ml of water, and saturated sodium chloride solution (30 ml), then dried with magnesium phosphate, filtered and indine and porate so as to give the compound corresponding to the title in the form of a yellow foam, with almost quantitative yield. Thin layer chromatography on silica: Rf = 0.57 (ethyl acetate). The product consisted of a mixture of geometric isomers (in the ratio of about 1/1, 4) around the double bond of the enamine. Nuclear magnetic resonance

Example 9

1- (3-phenoxymethyl-7-oxo-4-thia-2, 6-diazabicyclo (3,2, 0 pt-2-en-6-yl) -1- (para-nitrobenzyloxycarbonyl) -prop-1-en -2-diphenylphosphinate To a stirred solution of para-nitrobenzyl alpha- (3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo (3,2,0) hept-2-en-6-yl) -alpha- (1-hydroxyietiidene) acetate (4.69 g) in tetrahydrofuran (60 ml), under nitrogen atmosphere at a temperature from 0 to 5 ° C 1.6 ml of triethylamine were added, followed by the addition of 2, 73 g diphenylphosphinyl chloride, drop by drop over a period of 5 minutes. After stirring for 3 hours at 20 ° C, the tetrahydrofuran was evaporated off and then the residue was dissolved in dichloromethane. The resulting solution was then washed with acid 1% hydrochloric acid and then with water, then dried with magnesium sulphate and then evaporated to give the compound corresponding to the title in the form of a pale yellow friable foam, with essentially gloving yield. silica:

Rf = 0.54 (ethyl acetate), Nuclear magnetic resonance: _

_

_

Example 10

clo (3, 2, 0) hept-2-en-6-yl) -1- (para-nitrobenzyloxycarbonyl) prop-1-en-2-yl phenylphosphonate

To a stirred solution of para-nitroberisii alpha- (3-phenoxymethyl-7-oxo-4-thia-2, 6-diazabicyclo (3, 2, 0) hept-2-en-6-yl) -alpha- (1 -hydroxyethylidene) acetate (4.69 g) in 60 ml of tetrahydrofuran under nitrogen atmosphere at 0 ° C, 1.6 ml of triethylamine were added followed by? addition of 2.91 g of phenylphenylphosphonyl chloride. After shaking for

3 hours at 20 ° C the tetrahydrofuran was removed by evaporation and then the residue was dissolved in dichloromethane. The resulting solution was then washed with hydrochloric acid at 1? 1% and then with water, dried with magnesium sulphate and then evaporated so as to give the compound corresponding to the title in the form of a pale yellow, spinable foam, with essentially quantitative yield.

Thin layer chromatography of silica: Rf = 0, 64 (ethyl acetate) nuclear magnetic resonance

Example 1 1

To a stirred solution of tenzhydryl alpha- (3-benzyl-7-oxo-4-thia-2,6-diazabicyclo (3,2,0) hept-2-en-6-yl) -alpha- (1-hydroxyethylidene ) acetate (2.42 g) in 30 ml of tetrahydrofuran under nitrogen atmosphere at 20 ° C 0.74 ml of triethylamine were added followed by the addition of 1.09 ml of diphenylphosphoryl chloride. After stirring for 2 hours at a temperature of 20 ° C, the reaction mixture was diluted with dichloromethane, washed with brine, dried with magnesium sulfate and then evaporated to give the compound corresponding to the title in the form of a foam of pale yellow color with essentially quantitative yield. Thin layer chromatography of silica gave Rf = 0.58 (ethyl acetate) nuclear magnetic resonance

3

Example 12

To a stirred solution of

acetate (2.33 g) in 30 ml of tetrahydrofuran under nitrogen atmosphere at 20 ° C, 0.74 al of triethylamine were added followed by the addition of 1.09 ml of diphenylphosphon chloride. After stirring for 1.75 hours at 20 ° C the reaction mixture was diluted. ta with dichloromethane, washed with brine, dried with magnesium sulphate and then evaporated so? to give the compound corresponding to the title in the form of a pale yellow foam with essentially quantitative yield. Thin layer chromatography of silica gave Rf = 0.63 (ethyl acetate). The product consisted of a mixture of the geometric isomers (ratio of about 3/1) around the double bond of the enol phosphate. Nuclear magnetic resonance

Example 13

Para-nitrobenzyl alpha- (3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo (3,2,0) -ept-2-en-6-yl) -alpha- (1-morpholinoethylidene) acetate To a stirred solution of 1- (3-phenoxylimethyl-7-oxo-4-thia-2,6-diazabicyclo (3,2,0) hept-2-en-6-yl) -1- (para-nitrobenzyloxycarbonyl) -prop-1-en-2-yl diphenylphosphinate (1.34 g) in tetrahydrofuran (20 m) at a temperature from 0 to 5 ° C 0.38 ml of morpholine were added. After having stirred for 6 hours at an emperature from 0 to 5 ° C, the solvent was removed by evaporation and then the residue was dissolved in dichloromethane. The resulting solution was washed with water and then with saturated sodium chloride solution, then dried with magnesium sulfate and then evaporated to give the compound corresponding to the title in the form of a pale yellow foam with essentially quantitative yield. The product obtained was a mixture of the geometric isomers (ratio of about 1 / 1.4) around the double bond of the enamine and was identical to that obtained in Example 8.

Example 14

Para-nitrobenzyl alpha- (3-phenoxymethyl-7-oxo-4- thia-2,6-diazabicyclo (3,2,0) hept-2-en-6-yl) -alpha- (1-morpholinoethylidene) acetate Ad a stirred addition of phenyl 1- (3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo (3,2,0) -ept-2-en-6-yl) -1- (para-nitrobenzyloxycarbonyl ) -prop-1-en-2-yl phenylphosphonate (1.37 g) 0.383 ml of morpholine were added in 20 ml of tetrahydrofuran at a temperature of from 0 to 5 ° C, After stirring for 3 hours at a temperature of from 0 to 5 ? C, the solvent was e

vaporized and then the residue was dissolved in dichloromethane. The resulting solution was then washed with water and finally with saturated sodium chloride solution, then dried over magnesium sulfate and then evaporated to give the compound corresponding to the title in the form of a pale yellow foam with essentially quantitative yield. The product obtained was a mixture of the geometric isomers in the ratio of about 1 / 1.4 around the double bond of the enamine and was identical to that obtained in Example 8.

Example 15

ara-nitrobenzyl alpha- (3-benzyl-7-oxo-4-thia-2,6-diazabicyclo (3,2,0) hept-2-en-6-yl) -alpha- (1-piperidine-ethylidene) acetate To a stirred solution of para-nitrobenzyl alpha- (3-benzyl-7-oxo-4-thia-2,6-diazabicyclo (3,2,0) hept-2-en-6-yl) -alpha- ( 1-hydroxyethylidene) acetate (3.02 g) in 40 ml of tetrahydrofuran under nitrogen atmosphere at a temperature of 20 ° C, 0.98 ml of triethylamine were added followed by the addition of 1.45 ml of diphenyl phosphoryl chloride. stirred for 2 hours, the reaction mixture was cooled to 0 ° C and then 0.76 ml of piperidine was added. After stirring for 3 hours at a temperature from 0 to 5 ° C, the tetrahydrofuran was removed by evaporation and then the residue was dissolved in dichloromethane. The resulting solution was washed with water and then with a saturated sodium chloride solution, then dried with magnesium sulfate and then evaporated to give the compound corresponding to the title in the form of a pale yellow foam, with essentially quantitative yield. Chromatography on a thin layer of silica: Rf - 0.4-8 (dichloromethane-ethyl acetate 15/2). The product consisted of a mixture of the geometric isomers around the double bond of the enol phosphate. Nuclear magnetic resonance

Example 16

2,2,2-trichloroethyl alpha- (3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo (3,2,0) hept- 2-en-6-yl) -alpha- (1- morpho linoethylidene) acetate To a stirred solution of 2,2.2-trichloroethyl alpha- (3-phenoxymethyl-7-oxo-4-thia-2, diazabicyclo (3,2,0) hept-2-en-6-yl) - alpha- (1-hydroxyethylidene) acetate (2.33 g) 0.74 ml of tri

ethylamine followed by the addition of 1.09 ml of diphenylphosphoryl chloride. After stirring for 2 hours the reaction mixture was cooled down to 0 ° C and then 0.92 ml of morpholine were added. After stirring for 2 hours at 0 to 5 ° C, the tetrahydrofuran was removed by evaporation and then the residue was dissolved in dichloromethane. The resulting solution was washed with water and then with saturated sodium chloride solution, then dried with magnesium sulfate and then evaporated to give the compound corresponding to the title in the form of a pale yellow foam, with essentially quantitative yield. the eromatography on a thin layer of silica gave Rf = 0.20 dichloromethane / ethyl acetate = 15/2). The product consisted of a mixture of the geometric isomers (about 1.5 / 1) around the double bond of the enol phosphate. Nuclear magnetic resonance

Example 17

Para-nitrobenzyl alpha- (3-phenoxymethyl-7-oxo-4 thia-2,6-diazabicyclo (3,2,0) -ept-2-en-6-yl) -alpha- (1-morpholinoethylidene) acetate

To a stirred solution of para-nitroben -zyl alpha- (3-phenoxymethyl-7-oxo-4 thia-2,6-diazabyclo (3,2,0) hept-2-en-6-yl) -alpha- ( 1-hydroxyethylden) -acetate (4.69 g) 1.6 ml of triethylamine were added in 60 ml of tetrahydrofuran under nitrogen atmosphere at a temperature from 0 to 5C, followed by the addition of 1.36 ml of ethyl drop by drop. dichlorophosphate over a period of 5 minutes. After stirring for 3 hours at a temperature of 20 ° C, the reaction mixture was cooled down to a temperature of 0 ° C and then 4.0 ml of morpholine were added dropwise in a time of 10 minutes, the reaction temperature being maintained at the value from 0 to 5? C. After stirring for 3 hours at this temperature, the tetrahydrofuran was removed by evaporation and then the residue was dissolved in dichloromethane. the resulting solution was washed with water and then with saturated sodium chloride solution, then dried with magnesium sulfate and then evaporated to give the compound corresponding to the title in the form of a pale yellow foam, with essentially quantitative yield. The product obtained was a mixture of the geometric isomers in the ratio of about 1 / 1.4, around the double bond of the enamine and was, iden

identical to that obtained in Example 8.

Example 18

Para-nitrobenzyl alpha- (3-phenoxymethyl-7-oxo-4-thia-

2,6-diazabicyclo (3,2,0) hept-2-en-6-yl) -alpha- (1-morpholinoethyliden) acetate

To a stirred solution of para-nitrobenzyl alpha- (3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo (3,2,0) hept-2-en-6-yl) -alpha- (1 -hydroxyethylidene)

acetate (4.69 g) in a volume of 60 ml of tetrahydrofuran under nitrogen atmosphere at a temperature from 0 to 5 ° C, 1.6 ml of triethylamine were added, if

followed by the dropwise addition of 4.63 ml phenylphosphonic acid dichloride, over a period of 5 minutes. After shaking for 3 hours at 20? C,

the reaction mixture was cooled to 0 ° C and then 4.0 ml of morpholine was added dropwise over 10 minutes, the temperature of the

reaction being maintained at 0-5 ° C, After stirring

for 3 hours at this temperature, the tetrahydrofuran was removed by evaporation and then the residue was dissolved in dichloromethane. The resulting solution was then washed with water and then with

saturated solution of sodium cloide, dried with magnesium sulfate and then evaporated to give

the compound corresponding to the title in the form of a pale yellow foam with quantitative yield. The product obtained was a mixture of the geometric isomers (about 1 / 1.4) around the double bond of the enamine and was identical to that obtained in Example 8.

Example 19

Para-nitrobenzyl alpha- (3phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo (3,2,0) hept-2-en-6-yl) -alpha- (1-morpholinoethylidene) acetate One solution agitated para-nitrobenzyl alpha - (3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo (3,2,0) hept-2-en-6-yl) -alpha- (1-hydroxyethylidene) Acetate (4.69 g) in 60 ml of tetrahydrofuran under nitrogen atmosphere at a temperature from 0 to 5 ° C 1.6 ml of triethylamine were added followed by the addition carried out drop by drop of 1.72 ml of phenyldichlorophosphate over a period of 5 minutes. After stirring for 3 hours at 20 ° C, the reaction mixture was cooled to 0 ° C then 4.0 ml of morpholine were added dropwise in 10 minutes, the reaction temperature being kept at 0 to 5 ° C. After stirring for 3 hours at this temperature, the tetrahydrofuran was evaporated off and then the residue was dissolved in dichloromethane. The resulting solution was washed with water and then with saturated sodium chloride solution, then dried with magnesium sulfate and then evaporated so as to give the compound corresponding to the title as a yellow foam with essentially quantitative yield. The product obtained was a mixture of geometric isomers (about 1 / 1.4) around the anamine double bond, and was identical to that obtained in Example 8.

Example 20

Benzhydryl 7-phenylacetamido -3-hydroxy-3-cephem-4-carboxylate

To a stirred solution of benzhydryl alpha- (3-benzyl-7-oxo-4-thia-2,6-diazabicyclo (3, 2,0) hept-2-en-6-yl) - alpha- (1-hydroxyethylidene ) acetate (9T, 8 g) in 120 ml of tetrahydrofuran under an azo atmosphere? 2.93 ml of triethylamine were added at 20 ° C, carried out by adding 4.35 ml of diphenylphosphoryl chloride. After shaking for 3 hours, it raf? chilled the reaction mixture to 5-10 ° C. then 3.75 ml of morpholine were added and the mixture was stirred for 2 hours at a temperature of from 5 to 10 ° C. After cooling to -30 to -35 ° C, 1.62 ml of pyridine was added followed by 1.00 ml of bromine, added dropwise over 10 minutes. The reaction mixture was stirred at -30 to -35 ° C for 20 minutes and then 144 ml of 5% hydrochloric acid was added. After stirring at 20 ° C for 1 1/2 hours the reaction mixture was extracted with ethyl acetate and then the extract was washed with water, dried with magnesium sulfate and then evaporated thereby. to give a quantity? of foam of 10.3 g. 9.3 g of the foam were purified by means of chromatography on a silica gel column (600 g) with dichloromethane / acetone in the ratio 20/1 used as eluent medium. to give 7.04 g (78%) of the compound corresponding to the title in the form of a foam. Thin layer chromatography of silica gave Rf = 0.55 (ethyl acetate). Nuclear magnetic resonance

Example 21

Para-nitrobenzyl 7-phenoxyacetamido-3-hydroxy-3-cefem-4-carboxylate To a stirred solution of para-nitrobenzyl alpha- (3-phenoxymethyl-7-oxo-4-thia-2,6-d? Azabicyclo (3 , 2,0) ep -2-en-6-yl) -alpha- (1-hydroxyethylidene) acetate (9.36 g) in 120 ml of tetrahydrofuran under nitrogen atmosphere at 20 ° C, 3.21 ml of triethylamine followed by 5.82 g of phenylphenylpho

sfonyl chloride. After stirring for 2 hours at 20 ° C the reaction mixture was cooled to 0 ° C and 4.01 ml of morpholine was then added. After stirring for 2 and a half hours at 0 to 5 ° C, the mixture was cooled down to -30 ° C and also down to -35 ° C and then added 1.62 ml of pyridine, followed by addition, dropwise, of 1.00 ml of bromine over a period of 10 minutes. The reaction mixture was stirred at a temperature of 30 to -35 ° C for 20 minutes and then 144ml of 5% hydrochloric acid was added.After stirring at 20 ° C overnight the mixture was extracted with dichloromethane and then the extracts were washed with water and saturated sodium chloride solution, dried with magnesium sulphate and then evaporated to dryness. The residue was dissolved in ml of glacial acetic acid then the resulting solution was stirred for about 10 minutes in order to crystallize the product. Crystallization was completed by adding 120 ml of isopropanol in half an hour. The crystals were isolated by filtration, then washed with isopropanol and then dried under vacuum at 40 ° C overnight. The yield of para-nitrobenzyl 7-phenoxyacetamido-3-hydroxy-3cefem-4-carboxylate solvate with acetic acid was 8.29 g (76%).

Example 22

4-methoxybenzyl 7-phenoxyacetamido -3-hydroxy-3-cefem-4-carboxylate

To a stirred solution of 4-methoxybenzyl alpha- (3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo (3,2,0) pt-2-en-6-yl) -alpha- (1 -hydroxyethylidene) acetate (4.44 g) in 60 ml of tetrahydrofuran, under nitrogen atmosphere at 0 ° C, triethylamira (1.6 ml) was added followed by the addition of diphenylphosphoryl chloride (2.39 ml). After stirring for 3 hours at 0 to 5 ° C, 2.0 ml of morpholine was added and then the reaction mixture was stirred for another 3 hours at 0-5 ° C. The mixture was cooled to -30 to -35 ° C and then 0.81 ml of pyridine was added, followed by the dropwise addition of 0.5 ml of bromine over a period of 5 minutes, the mixture of reaction was stirred at -30 to -35 ° C for 20 minutes and then added 72 ml of 5% hydrochloric acid, followed by the addition of 60 ml of methanol. After stirring overnight at room temperature, the mixture was extracted with dichloromethane and then the extract was washed with water, dried with magnesium sulfate and then evaporated. The residual rubber was subjected to chromatography on silica gel (300 g), with dichloromethane / acetone (9/1) used as the eluent medium so? to give 3.6 g (76.6 / 0) of 4-methoxybenzyl 7-phenoxyacetamido-3-hydroxy-3-cefem-4-carboxylate as foam. Thin layer chromatography of silica gave Rf = 0.5 (toluene / ethyl acetate = 1/1). Nuclear magnetic resonance-

Example 23

2,2,2-trichloroethyl 7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylate To a stirred solution of 2,2,2-trichloroethyl alpha- (3-phenoxymethyl-7-oxo-4-thia-2 , 6-diazabicyclo (3,2,0) hept-2-en-6-yl) -alpha- (1-hydroxyethylidene) -acetate (2,33 g) in a volume of 30 ml of tetrahydrofuran under a nitrogen atmosphere at 20 ° C, 0.74 ml of triethylamine are added followed by the addition of 1.09 ml of diphenylphosphoryl chloride. After stirring for 2 hours, the reaction mixture was cooled to 0 ° C, then 0.92 ml of morpholine was added and the reaction mixture was stirred for 3 hours at 0 to 5 ° C. The mixture was cooled to -30 to -35 ° C, and then 0.42 ml of pyridia was added, followed by the dropwise addition of 0.25 ml of bromine over a period of 5 minutes. The reaction mixture was stirred at -30 to -35 ° C for 20 minutes and then 60 ml of hydrochloric acid was added. After stirring for 2 hours at room temperature, the mixture was extracted with ethyl acetate and then extract was washed with water, dried with magnesium sulfate and then evaporated thus? to give a yellow foam. The foam was purified by column chromatography of silica gel (100 g) with dichloromethane / acetone (25/1) used with eluent medium, so. to give a quantity? 1.8 g (74.7%) of 2, 2, 2-trichloroethyl 7-phenoxy acetamido-3-hydroxy-3-cefem-4-carboxylate as a foam. Thin layer chromatography of silica: Rf = 0.2 (toluene / ethyl acetate = 1/1). MRI nu?

Claims (8)

1. Process for producing an enamine of formula IX: where R? a protective group of the carboxylic acid and? the residue of an acyl group derived from a carboxylic acid and and are identical or different and are alkyl groups having 1 to 4 carbon atoms or aralkyl groups having 7 to 10 carbon atoms; that is, taken together with the nitrogen atom in an adjacent position, they form a heterocyclic ring which contains a number of carbon atoms ranging from 4 to 8, and optionally a further heteroatom which is selected from oxygen and nitrogen; by reacting an enol of formula XI: with a phosphorus reagent of formula VII: where they are identical or different they can each represent a phenyl group or a phenoxy group, optionally substituted with a number of groups from 1 to 3 selected from an alkyl radical having from 1 to 4 alkoxy radial carbon atoms having from 1 to 4 carbon atoms, halogen and nitro group; or an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, a cycloalkoxyl group having 3 to 8 carbon atoms, chlorine or bromine; X? an atom of chlorine, bromine, an itryl group or an azide group; provided that: - i) and cannot both be a- tomes of halogen; And ii) when X? a nitrile group or an azide group are identical or different and are phenoxy groups; cycloalkoxy or alkoxy groups of 1 to 4 carbon atoms so as to form a product of formula XII: operation followed by the reaction of this product with an amine of the formula cos? to form the enamine of formula IX. 2. Process according to claim 1, where a reagent of formula VII is used in which phenoxy groups are optionally substituted with one to three groups selected from an alkyl radical having from 1 to 4 carbon atoms, alkoxy having from 1 to 4 atoms of carbon, halogen and nitro group; alkoxy radical having from 1 to 4 carbon atoms or cycloalkyloxy radical having d? 3 to 8 carbon atoms and X? bromine or chlorine. 3. The process of claim 2 wherein are phenoxy groups,? a para-nitrobenzyl group? a benzyl or phenoxymethyl group, taken together with the adjacent nitrogen atom represent a morpholino group and X? an atom of chlorine. 4. Enamine of formula IX when the same is produced by a process according to any one of the preceding claims 1 to 3. 5. Procediment for producing a 3-hydroxycephalus sporine of formula VIII: where and are they as gi? ? is defined in any one of the preceding claims 1 to 3, which method comprises: a) the halogenation of a compound of foraula IX how? been defined in claim 1, and. b) cyclization of the halogenated product (X) where X? an atom of chlorine, bromine or iodine, co s? to give the 3-hydroxycephalosporin of formula VIII 6. Process of claim 5 wherein the halogenation reaction in step a) is carried out with molecular bromine 7. 3-hydroxycephalosporin when the same is prepared by the process according to claims 5 or 6. 8. Compound of formula XII: where are they like gi? ? been defined in any one of the preceding claims 1 to 3, in the form (E) - or (Z) -9. Compound of formula XII, as claimed in claim 8 in which are phenoxy radicals, and a para-nitrobenzyl group and R3? a benzyl group or a phenoxymethyl group